Oncogenic HPV, mucosal immune response and risk of HIV acquisition. Approximately 33 million people are infected with HIV worldwide, with 2.7 million new infections in 2008 alone. The infection disproportionately affects sub-Saharan Africa with 67% of all HIV infections and 75% of all HIV/AIDS deaths. High-risk human papillomavirus (HR-HPV) infection leads to anogenital cancers, including cervical cancer (the third leading cause of cancer mortality in women worldwide). HR-HPV may also be a risk factor for HIV acquisition, presumably due to recruitment of HIV target cells into the mucosa. However, the genital mucosal immunologic microenvironment and HIV/HR-HPV interactions are poorly understood. Male circumcision reduces the risk of HIV and HR-HPV, demonstrating the critical role of the foreskin in acquisition and transmission of these viral infections. Foreskin tissue, genital swabs of men and their female partners, and epidemiologic data from male circumcisions in Rakai, Uganda, provide biological samples to assess HIV and HR-HPV mucosal immunologic interactions. We hypothesize that HR-HPV clearance induces a distinct proinflammatory cytokine/chemokine profile and increased foreskin mucosal T-cell densities which are associated with increased risk of HIV acquisition. We propose the following aims. 1) Assess whether clearance of pre-existing HR-HPV infection and/or acquisition of a new HR-HPV genotype are associated with an increased risk of HIV acquisition in men and women using a case-control design in which cases will be HIV seroconverters and controls will be persistently HIV-negative individuals. 2) Characterize the foreskin cellular mucosal immunologic response associated with HR-HPV in HIV+ and HIV-negative men. 3) Compare cytokine/chemokine concentrations in penile swabs associated with HR-HPV and HIV infection status. <4) Determine whether increased foreskin immunologic cell densities and penile proinflammatory cytokines/chemokines are associated with HR-HPV clearance.>The foreskin mucosa, genital swabs and epidemiologic data provide a unique opportunity to study HIV and HR-HPV infection and could potentially inform the development of HIV preventive measures. This K23 grant will contribute to the professional and scientific development of a physician scientist. The applicant has completed an NIH-funded MD/PhD program and a clinical pathology residency. This grant will enable the applicant to develop proficiency in epidemiology and biostatistics and, building on the proposed research program, to design and manage an independent RO1-level research program in molecular/clinical epidemiology. The applicant will utilize the strengths of his mentors and the Rakai Health Science Program in Uganda (one of the largest and longest-running population-based HIV and infectious diseases cohorts in sub- Saharan Africa) to learn how to design, implement, manage and analyze international HIV research studies. PUBLIC HEALTH RELEVANCE (provided by applicant): High-risk human papillomavirus (HR-HPV) infection may be a risk for HIV acquisition by recruiting T cells to the genital mucosa. However, little is known about the genital mucosal immune response to HR-HPV and HIV infection, especially in men. Male circumcision trials provide access to foreskin genital mucosa and genital swabs permit cytokine/chemokine measurements. An improved understanding of the mucosal immune milieu associated with HIV and HR-HPV infection could have an impact on future HIV prevention. If our hypothesis is supported by this study, it will provide the rationale for future HIV prevention trials, potentially employing HR-HPV vaccines.